Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts

Oncogenesis
Chun-Hau ChenRupal S Bhatt

Abstract

Several therapeutic options are available for metastatic RCC, but responses are almost never complete, and resistance to therapy develops in the vast majority of patients. Consequently, novel treatments are needed to combat resistance to current therapies and to improve patient outcomes. We have applied integrated transcriptome and proteome analyses to identify cathepsin B (CTSB), a cysteine proteinase of the papain family, as one of the most highly upregulated gene products in established human RCC xenograft models of resistance to vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). We used established RCC models to test the significance of CTSB in the progression of renal cancer. Our evaluation of CTSB showed that stable CTSB knockdown suppressed RCC growth in vitro and in vivo. Stable over-overexpression of wild-type CTSB (CTSBwt/hi), but not of an CTSB active site mutant (CTSBN298A), rescued cell growth in CTSB knockdown cells and abolished the efficacy of VEGFR TKI treatment. Genome-wide transcriptome profiling of CTSB knockdown cells demonstrated significant effects on multiple metabolic and stem cell-related pathways, with ALDHA1A (ALDH1) as one of the most significantly downregulated ge...Continue Reading

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Citations

May 20, 2020·Expert Review of Proteomics·Francesca Raimondo, Marina Pitto
Apr 26, 2020·International Journal of Molecular Sciences·Chia-Liang LinChien-Min Chen
Dec 19, 2020·International Journal of Molecular Sciences·Eun-Kyung KimYoo Seung Chung

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Methods Mentioned

BETA
xenografts
xenograft
PCR
RNASeq
transfection
flow cytometry
proteomic

Software Mentioned

GraphPad Prism
GraphPad
LIMMA
R
IPA
ProteinPilot

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